The discovery and characterization of both oncogenes and TSGs represented outstanding achievements in the understanding of the molecular pathogenesis of cancer. An important step in this process has been the elucidation of the mechanisms by which proto-oncogenes are activated to oncogenes and TSGs are inactivated, resulting in the uncontrolled growth that characterizes cancer cells. Further investigations on oncogenes made it clear that their activation in cancer cells can be ascribed to several different mechanisms, as follows:
1. Structural alterations of the genes:
• Point mutations
• Chromosomal translocations, such as the t(9;22) in chronic myeloid leukemia
2. Gene amplification (e.g., NMYC amplification in neuroblastoma) evidenced as either
• Small separate chromosomes (double minutes) or
• Insertions within normal chromosomes (homogeneously staining regions, or HSR)
3. Loss of appropriate control mechanisms, by either
• Chromosome translocation (translocation of the MYC gene on chromosome 8 to one of the immunoglobulin loci on chromosome 14 in Burkitt's lymphoma) or
• Insertional mutagenesis (insertion of a DNA copy of a retrovirus into the cellular genome close to a proto-oncogene)29
Despite the reported variety of the mechanisms involved in the activation of proto-oncogenes, the proposed mechanisms of inactivation of TSGs has remained limited to the structural alteration evolving from a single base (point mutation) to wider portions of the genome. With the increasing interest in TSGs and the potential application of genetic testing to the early diagnosis or identification of predisposition to cancer, the role of mutations in cancer development has become increasingly relevant. Indeed, most researchers worldwide acknowledge no "cause" of cancer other than mutation.
In one of the following paragraphs on gene methylation, we will see that the close relationship between mutations and cancer should be viewed with a more relativistic eye, since gene expression may be altered even in the absence of structural alterations of genes. Moreover, considering the complexity of cell structure and function, and the number of different environmental influences a cell undergoes during its vital cycle, limiting the possible molecular pathogenesis of cancer to one or two mutations within a single gene, as in the case of retinoblastoma, appears to be a very restricted view of the problem.
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